Skip to main content
SpringerLink
Log in

Endoplasmic Reticulum Stress Upregulates the Chondroitin Sulfate Level which thus Prevents Neurite Extension in C6 Glioma Cells and Primary Cultured Astrocytes

  • Original Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Chondroitin sulfate (CS), which is known to be a neurite-preventing molecule, is a major component of the extracellular matrix (ECM) in the central nervous system (CNS). The CS expression is upregulated around damaged areas. Endoplasmic reticulum (ER) stress causes neuronal cell death in numerous neurodegenerative diseases. However, the effects of ER stress on glial cells remain to be clarified. The present study examined whether direct ER stress to glial cells can upregulate CS expression in C6 glioma cells and primary cultured mouse astrocytes, and also whether the expression of CS prevents neurite extension. ER stressors tunicamycin (TM) and thapsigargin (TG) significantly increased CS expression in both C6 cells and primary cultured astrocytes, while NO donor sodium nitroprusside (SNP) did not significantly alter the CS expression. The dosage of TM and TG treatment used in this study did not significantly induce cell death but upregulated the ER chaperone molecule Grp78 in C6 glioma cells and primary astrocytes. The ECM of glial cells exposed to ER stress prevented neurite extension in primary cultured mouse cortical neurons, and chondroitinase ABC (ChABC) treatment diminished the inhibitory effect on neurite extension. These findings suggest that direct ER stress to glial cells increases the CS expression, which thus prevents neurite extension.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Apelt J, Schliebs R (2001) β-Amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology. Brain Res 894:21–30

    Article  PubMed  CAS  Google Scholar 

  • Asher RA, Morgenstern DA, Fidler PS, Adcock KH, Oohira A, Braistead JE, Levine J M, Margolis RU, Rogers JH, Fawcett JW (2000) Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J Neurosci 20:2427–2438

    PubMed  CAS  Google Scholar 

  • Baig S, Wilcock GK, Love S (2005) Loss of perineuronal net N-acetylgalactosamine in Alzheimer’s disease. Acta Neuropathol 110:393–401

    Article  PubMed  CAS  Google Scholar 

  • Barritt AW, Davies M, Marchand F, Hartley R, Grist J, Yip P, McMahon SB, Bradbury EJ (2006) Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci 26:10856–10867

    Article  PubMed  CAS  Google Scholar 

  • Bignami A, Perides G, Rahemtulla F (1993) Versican, a hyaluronate-binding proteoglycan of embryonal precartilaginous mesenchyma, is mainly expressed postnatally in rat brain. J Neurosci Res 34:97–106

    Article  PubMed  CAS  Google Scholar 

  • Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416:636–640

    Article  PubMed  CAS  Google Scholar 

  • Busch SA, Silver J (2007) The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17:120–127

    Article  PubMed  CAS  Google Scholar 

  • Cacquevel M, Lebeurrier N, Chéenne S, Vivien D (2004) Cytokines in neuroinflammation and Alzheimer’s disease. Curr Drug Targets 5:529–534

    Article  PubMed  CAS  Google Scholar 

  • Caggiano AO, Zimber MP, Ganguly A, Blight AR, Gruskin EA (2005) Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma 22:226–239

    Article  PubMed  Google Scholar 

  • Canas N, Valero T, Villarroya M, Montell L, Verges J, Garcia AG, Lopez MG (2007) Chondroitin sulphate protects SH-SY5Y cells from oxidative stress by inducing Heme Oxygenase-1 via PI3K/Akt. J Pharmacol Exp Ther 323:946–953

    Article  PubMed  CAS  Google Scholar 

  • Carulli D, Rhodes KE, Brown DJ, Bonnert TP, Pollack SJ, Oliver K, Strata P, Fawcett JW (2006) Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J Comp Neurol 494:559–577

    Article  PubMed  CAS  Google Scholar 

  • Clement AM, Sugahara K, Faissner A (1999) Chondroitin sulfate E promotes neurite outgrowth of rat embryonic day 18 hippocampal neurons. Neurosci Lett 269:125–128

    Article  PubMed  CAS  Google Scholar 

  • Clement AM, Nadanaka S, Masayama K, Mandl C, Sugahara K, Faissner A (1998) The DSD-1 carbohydrate epitope depends on sulfation, correlates with chondroitin sulfate D motifs, and is sufficient to promote neurite outgrowth. J Biol Chem 273:28444–28453

    Article  PubMed  CAS  Google Scholar 

  • Dewitt DA, Silver J (1996) Regenerative failure: a potential mechanism for neuritic dystrophy in Alzheimer’s disease. Exp Neurol 142:103–110

    Article  PubMed  CAS  Google Scholar 

  • Ferreiro E, Resende R, Costa R, Oliveira CR, Pereira CM (2006) An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis 23:669–678

    Article  PubMed  CAS  Google Scholar 

  • Flanders KC, Ren RF, Lippa CF (1998) Transforming growth factor-betas in neurodegenerative disease. Prog Neurobiol 54:71–85

    Article  PubMed  CAS  Google Scholar 

  • Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54:1–18

    Article  PubMed  CAS  Google Scholar 

  • Gupta-Bansal R, Frederickson RC, Brunden KR (1995) Proteoglycan-mediated inhibition of A beta proteolysis. A potential cause of senile plaque accumulation. J Biol Chem 270:18666–186671

    Article  PubMed  CAS  Google Scholar 

  • Hagihara K, Miura R, Kosaki R, Berglund E, Ranscht B, Yamaguchi Y (1999) Immunohistochemical evidence for the brevican-tenascin-R interaction: colocalization in perineuronal nets suggests a physiological role for the interaction in the adult rat brain. J Comp Neurol 410:256–264

    Article  PubMed  CAS  Google Scholar 

  • Haunso A, Celio MR, Margolis RK, Menoud PA (1999) Phosphacan immunoreactivity is associated with perineuronal nets around parvalbumin-expressing neurons. Brain Res 834:219–222

    Article  PubMed  CAS  Google Scholar 

  • Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol (Berl) 110:165–172

    Article  CAS  Google Scholar 

  • Hu J, Akama KT, Krafft GA, Chromy BA, Van Eldik LJ (1998) Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res 785:195–206

    Article  PubMed  CAS  Google Scholar 

  • Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M (2004) Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat 28:67–78

    Article  PubMed  CAS  Google Scholar 

  • Kosuge Y, Sakikubo T., Ishige K, Ito Y (2006) Comparative study of endoplasmic reticulum stress-induced neuronal death in rat cultured hippocampal and cerebellar granule neurons. Neurochem Int 49:285–293

    Article  PubMed  CAS  Google Scholar 

  • Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392

    Article  PubMed  CAS  Google Scholar 

  • Matsui F, Nishizuka M, Yasuda Y, Aono S, Watanabe E, Oohira A (1998) Occurrence of a N-terminal proteolytic fragment of neurocan, not a C-terminal half, in a perineuronal net in the adult rat cerebrum. Brain Res 790:45–51

    Article  PubMed  CAS  Google Scholar 

  • McLaurin J, Fraser PE (2000) Effect of amino-acid substitutions on Alzheimer’s amyloid-β peptide-glycosaminoglycan interactions. Eur J Biochem 267:6353–6361

    Article  PubMed  CAS  Google Scholar 

  • Miyata S, Nishimura Y, Nakashima T (2007) Perineuronal nets protect against amyloid β-protein neurotoxicity in cultured cortical neurons. Brain Res 1150:200–206

    Article  PubMed  CAS  Google Scholar 

  • Momoi T (2006) Conformational diseases and ER stress-mediated cell death: apoptotic cell death and autophagic cell death. Curr Mol Med 6:111–118

    Article  PubMed  CAS  Google Scholar 

  • Moon LD, Asher RA, Rhodes KE, Fawcett JW (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci 4:465–466

    PubMed  CAS  Google Scholar 

  • Morawski M, Bruckner MK, Riederer P, Bruckner G, Arendt T (2004) Perineuronal nets potentially protect against oxidative stress. Exp Neurol 188:309–315

    Article  PubMed  CAS  Google Scholar 

  • Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674

    Article  PubMed  CAS  Google Scholar 

  • Novak U, Kaye AH (2000) Extracellular matrix and the brain: components and function. J Clin Neurosci 7:280–290

    Article  PubMed  CAS  Google Scholar 

  • Okamoto M, Mori S, Endo H (1994a) A protective action of chondroitin sulfate proteoglycans against neuronal cell death induced by glutamate. Brain Res 637:57–67

    Article  PubMed  CAS  Google Scholar 

  • Okamoto M, Mori S, Ichimura M, Endo H (1994b) Chondroitin sulfate proteoglycans protect cultured rat’s cortical and hippocampal neurons from delayed cell death induced by excitatory amino acids. Neurosci Lett 172:51–54

    Article  PubMed  CAS  Google Scholar 

  • Oohira A, Matsui F, Tokita Y, Yamauchi S, Aono S (2000) Molecular interactions of neural chondroitin sulfate proteoglycans in the brain development. Arch Biochem Biophys 374:24–34

    Article  PubMed  CAS  Google Scholar 

  • Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389

    Article  PubMed  CAS  Google Scholar 

  • Penas C, Guzman MS, Verdu E, Fores J, Navarro X, Casas C (2007) Spinal cord injury induces endoplasmic reticulum stress with different cell-type dependent response. J Neurochem 102:1242–1255

    Article  PubMed  CAS  Google Scholar 

  • Perez M, Wandosell F, Colaco C, Avila J (1998) Sulphated glycosaminoglycans prevent the neurotoxicity of a human prion protein fragment. Biochem J 335:369–374

    PubMed  CAS  Google Scholar 

  • Properzi F, Carulli D, Asher RA, Muir E, Camargo LM, van Kuppevelt TH, ten Dam GB, Furukawa Y, Mikami T, Sugahara K, Toida T, Geller HM, Fawcett JW (2005) Chondroitin 6-sulphate synthesis is up-regulated in injured CNS, induced by injury-related cytokines and enhanced in axon-growth inhibitory glia. Eur J Neurosci 21:378–390

    Article  PubMed  Google Scholar 

  • Reilly JF, Maher PA, Kumari VG (1998) Regulation of astrocyte GFAP expression by TGF-beta1 and FGF-2. Glia 22:202–210

    Article  PubMed  CAS  Google Scholar 

  • Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci 22:10690–10698

    PubMed  CAS  Google Scholar 

  • Saito A, Hino S, Murakami T, Kondo S, Imaizumi K (2007) A novel ER stress transducer, OASIS, expressed in astrocytes. Antioxid Redox Signal 9:563–71

    Article  PubMed  CAS  Google Scholar 

  • Salinero O, Moreno-Flores MT, Ceballos ML, Wandosell F (1997) β-Amyloid peptide induced cytoskeletal reorganization in cultured astrocytes. J Neurosci Res 47:216–223

    Article  PubMed  CAS  Google Scholar 

  • Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156

    Article  PubMed  CAS  Google Scholar 

  • Sirko S, von Holst A, Wizenmann A, Gotz M, Faissner A (2007) Chondroitin sulfate glycosaminoglycans control proliferation, radial glia cell differentiation and neurogenesis in neural stem/progenitor cells. Development 134:2727–2738

    Article  PubMed  CAS  Google Scholar 

  • Smith GM, Strunz C (2005) Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes. Glia 52:209–218

    Article  PubMed  Google Scholar 

  • Sotogaku N, Tully SE, Gama CI, Higashi H, Tanaka M, Hsieh-Wilson LC, Nishi A (2007) Activation of phospholipase C pathways by a synthetic chondroitin sulfate-E tetrasaccharide promotes neurite outgrowth of dopaminergic neurons. J Neurochem 103:749–760

    Article  PubMed  CAS  Google Scholar 

  • Sugahara K, Mikami T, Uyama T, Mizuguchi S, Nomura K, Kitagawa H (2003) Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr Opin Struct Biol 13:612–620

    Article  PubMed  CAS  Google Scholar 

  • Thon N, Haas CA, Rauch U, Merten T, Fassler R, Frotscher M, Deller T (2000) The chondroitin sulphate proteoglycan brevican is upregulated by astrocytes after entorhinal cortex lesions in adult rats. Eur J Neurosci 12:2547–2558

    Article  PubMed  CAS  Google Scholar 

  • Vawter MP, Dillon-Carter O, Tourtellotte WW, Carvey P, Freed WJ (1996) TGFbeta1 and TGFbeta2 concentrations are elevated in Parkinson’s disease in ventricular cerebrospinal fluid. Exp Neurol 142:313–322

    Article  PubMed  CAS  Google Scholar 

  • Woods AG, Cribbs DH, Whittemore ER, Cotman CW (1995) Heparan sulfate and chondroitin sulfate glycosaminoglycan attenuate beta-amyloid(25–35) induced neurodegeneration in cultured hippocampal neurons. Brain Res 697:53–62

    Article  PubMed  CAS  Google Scholar 

  • Yoshida H (2007) ER stress and disease. FEBS J 274:630–658

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Epigenetic Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, 409-3898, Japan

    Takamitsu Natori & Kaoru Nagai

Authors
  1. Takamitsu Natori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaoru Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kaoru Nagai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Natori, T., Nagai, K. Endoplasmic Reticulum Stress Upregulates the Chondroitin Sulfate Level which thus Prevents Neurite Extension in C6 Glioma Cells and Primary Cultured Astrocytes. Cell Mol Neurobiol 28, 857–866 (2008). https://doi.org/10.1007/s10571-008-9262-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-008-9262-5

Keywords

Search

Navigation